Project description:We investigated the impacts of environmental circadian disruption on placental gene expression (E15.5) in a C57BL/6J mouse (Mus musculus) model. A number of transcripts showed sex-specific patterns of expression and several transcripts were differentially expressed in placenta from mice developmentally exposed to circadian disruption compared to mice exposed to control light.
Project description:We report the emergence of an endogenous circadian clock in mouse fetal kidney that regulates organogenesis. We detect circadian rhythms both in vivo with transcriptional profiling and ex vivo by bioluminescence. High-resolution structural analysis of embryonic explants reveals that global or local clock disruption results in defects that resemble human congenital abnormalities of the kidney. The onset of fetal rhythms strongly correlates with the timing of a distinct transition in branching and growth rates during a gestational window of high fetal growth demands. Defects in clock mutants typically have been attributed to accelerated aging, however, our study establishes a role for the fetal circadian clock as a developmental timer that regulates the pathways that control organogenesis, branching rate and nephron number, and thus plays a fundamental role in kidney development.
Project description:Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined. We demonstrate that exposure to chronic circadian disruption (chronic jetlag, CJL) increases tumor formation in a mouse model of KRAS-driven lung cancer. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. Consistently, exposure to CJL disrupted the highly rhythmic nuclear trafficking of HSF1 in the lung, resulting in an enhanced accumulation of HSF1 in the nucleus. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis.
Project description:Circadian disruption has multiple pathological consequences, but the underlying mechanisms are largely unclear. To address such mechanisms, we subjected cultured cells to chronic circadian desynchrony (CCD), mimicking a chronic jet-lag paradigm, and assayed a range of cellular functions. The results indicated a specific circadian clock-dependent increase in cell proliferation. Transcriptome analysis revealed upregulation of G1-S-phase transition genes (cMyc, CyclinD1/3, Cdt1), concomitant with increased phosphorylation of the Retinoblastoma protein (Rb) by Cyclin D kinase 4/6 (CDK4/6) and increased G1-S progression. Phospho-Rb (Ser807/811) was found to oscillate in a circadian fashion and exhibit phase-shifted rhythms in circadian desynchronized cells. A CDK4/6 inhibitor approved for cancer treatment reduced growth of cultured cells and mouse tumors in a time-of-day specific manner, but the time dependence was lost with CCD. Our study identifies a mechanism that underlies effects of circadian disruption on tumor growth and underscores the importance of treatment timed to endogenous circadian rhythms.
Project description:The circadian rhythms influence the metabolic activity from molecular level to tissue, organ, and host level. Disruption of the circadian rhythms manifests to the host's health as metabolic syndromes, including obesity, diabetes, and elevated plasma glucose, eventually leading to cardiovascular diseases. Therefore, it is imperative to understand the mechanism behind the relationship between circadian rhythms and metabolism. To start answering this question, we propose a semimechanistic mathematical model to study the effect of circadian disruption on hepatic gluconeogenesis in humans. Our model takes the light-dark cycle and feeding-fasting cycle as two environmental inputs that entrain the metabolic activity in the liver. The model was validated by comparison with data from mice and rat experimental studies. Formal sensitivity and uncertainty analyses were conducted to elaborate on the driving forces for hepatic gluconeogenesis. Furthermore, simulating the impact of Clock gene knockout suggests that modification to the local pathways tied most closely to the feeding-fasting rhythms may be the most efficient way to restore the disrupted glucose metabolism in liver.
Project description:Disruption of the Circadian Clock within the Cardiomyocyte Influences Myocardial Contractie Function, Metabolism, and Gene Expression Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally-based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variations in myocardial biology. We therefore generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse, in order to test this hypothesis. At 12 weeks of age, CCM mice exhibit normal myocardial contractile function in vivo, as assessed by echocardiography. Radiotelemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted in CCM hearts perfused ex vivo in the working mode, highlighting the intrinsic nature of this phenotype. Wild-type, but not CCM, hearts exhibited a marked diurnal variation in responsiveness to an elevation in workload (80mmHg plus 1 microM epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase versus the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, while cardiac efficiency was decreased, in CCM hearts. These observations were associated with no alterations in mitochondrial content or structure, and modest mitochondrial dysfunction, in CCM hearts. Gene expression microarray analysis identified 548 and 176 genes in atria and ventricles, respectively, whose normal diurnal expression patterns were altered in CCM mice. These studies suggest that the cardiomyocyte circadian clock influences myocardial contractile function, metabolism, and gene expression. Keywords: Comparison of circadian oscillations in gene expression in hearts taken from wildtype and transgenic animals